Phosphorus-Promoted Photochemistry

Welcome to this week’s Organic Synthesis Newsletter.

Monday 23^rd September – Sunday 29^th September 2024

SCIENCE

Photochemical Phosphorus-Enabled Scaffold Remodeling of Carboxylic Acids

Q. Peng, M. U. Hwang, Á. Rentería-Gómez, P. Mukherjee, R. M. Young, Y. Qiu, M. R. Wasielewski, O. Gutierrez & K. A. Scheidt*

Science 2024, 385, 1471–1477 (DOI: 10.1126/science.adr0771)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-mg64g) 🔓

The excitation of carbonyl compounds by light to generate radical intermediates has historically been restricted to ketones and aldehydes; carboxylic acids have been overlooked because of high energy requirements and low quantum efficiency. A successful activation strategy would necessitate a bathochromic shift in the absorbance profile, an increase in triplet diradical lifetime, and ease of further functionalization. The authors present a single-flask transformation of carboxylic acids to acyl phosphonates that can access synthetically useful triplet diradicals under visible light or near-ultraviolet irradiation. The use of phosphorus circumvents unproductive Norrish type I processes, promoting selectivity that enables hydrogen-atom transfer reactivity. Use of this strategy promotes the efficient scaffold remodeling of carboxylic acids through various annulation, contraction, and expansion manifolds.

NATURE CHEMISTRY

Modular Alkene Synthesis from Carboxylic Acids, Alcohols and Alkanes via Integrated Photocatalysis

H. Zeng, R. Yin, Y. Zhao,* J.-A. Ma* & J. Wu*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01642-6)

Alkenes serve as versatile building blocks in diverse organic transformations. Despite notable advancements in olefination methods, a general strategy for the direct conversion of carboxylic acids, alcohols and alkanes into alkenes remains a formidable challenge. Here, the authors demonstrate an integrated photochemical strategy that facilitates a one-pot conversion of these fundamental building blocks into alkenes through a sequential C(sp³)–C(sp³) bond formation–fragmentation process, utilizing an easily accessible and recyclable phenyl vinyl ketone as the “olefination reagent”. This practical method not only offers an unparalleled paradigm for accessing value-added alkenes from abundant and inexpensive starting materials but also showcases its versatility through various complex scenarios, including late-stage on-demand olefination of multifunctional molecules, chain homologation of acids and concise syntheses of bioactive molecules.

Gold-Catalysed Amine Synthesis by Reductive Hydroamination of Alkynes with Nitroarenes

T. Zhou, P. Gao, R. Lalancette, R. Szostak & M. Szostak*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01624-8)

Amines are the most pivotal class of organic motifs in pharmaceutical compounds. Here, the authors provide a blueprint for a general synthesis of amines by catalyst differentiation enabled by triple Au–H/Au⁺/Au–H relay catalysis. The parent catalyst is differentiated into a set of catalytically active species to enable triple cascade catalysis, where each catalytic species is specifically tuned for one catalytic cycle. This strategy enables the synthesis of biorelevant amine motifs by reductive hydroamination of alkynes with nitroarenes. Using this triple cascade approach, exceptional functional group tolerance was achieved, enabling the use of bulk chemical feedstocks as coupling partners for the amination of both simple and complex alkynes (>100 examples), including those derived from pharmaceuticals, peptides and natural products (>30 examples).

NATURE SYNTHESIS

Palladium-Catalysed [2σ+2π] Cycloaddition Reactions of Bicyclo[1.1.0]butanes with Aldehydes

T. Qin,^† M. He^† & W. Zi*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00659-6)

Cycloaddition reactions of bicyclo[1.1.0]butanes (BCBs) with 2π components are a powerful tool for preparing C(sp³)-rich arene bioisosteres. Despite enormous progress in this field, catalytic enantioselective cycloadditions of BCBs that produce enantioenriched three-dimensional bioisosteres are underdeveloped. Here, the authors report a palladium-catalysed [3+2] cycloaddition reaction of vinyl-carbonyl-BCBs with carbonyl compounds, including formaldehyde, activated ketones, and aliphatic and aromatic aldehydes. This approach provides quick access to a wide variety of 2-oxabicyclo[2.1.1]hexanes and the practicality of the method was further demonstrated by carrying out several downstream transformations of the cycloaddition products.

Carbon Isotopic Labelling of Carboxylic Acids Enabled by Organic Photoredox-Catalysed Cyanation

Z. Zhu,^† X. Wu,^† G. T. Bida, H. Deng, X. Ma, S. Qian, Z. Wu, Z. Li* & D. A. Nicewicz*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00656-9)

The application of molecular imaging has advanced personalized medicine and generated a profound impact on patient care. Positron emission tomography and magnetic resonance imaging are among the most widely used imaging modalities, often requiring the isotopic labelling of bioactive molecules to generate the desired imaging probes. Unfortunately, radiochemistry often limits the development of novel agents due to complicated syntheses and the incompatibility of complex molecules. Here, considering the prevalence of carboxylic acids in drug and bioactive molecules, the authors have developed a method to perform ^11/13C labelling through carboxylic acid groups via organic photoredox reactions to generate radiolabelled nitriles. This strategy was applied to a range of aliphatic carboxylic acids, including complex and functionalized drug molecules, amino acids and short peptides. The radiolabelled nitrile products could be easily converted back to radiolabelled carboxylic acids with high radiochemical yields and molar activities.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Allenyl Thianthrenium Salt: A Bench-Stable C₃ Synthon for Annulation and Cross-Coupling Reactions

S. Tewari, N. Klask & T. Ritter*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10135) 🔓

The authors report the first bench-stable and non-hygroscopic mono-substituted allenyl sulfonium salt (ATT) synthesized from thianthrene and propargyl alcohol. ATT’s use has been demonstrated in annulation chemistry to synthesize heterocycles, such as 2-hydroxy morpholine, 2-methyl quinoxalines, and benzodioxepinone derivatives with an exocyclic double bond. The reagent is the first allenyl sulfonium salt that can undergo palladium-catalyzed cross-coupling reactions to form a C(sp²)–C(sp²) bond via Suzuki coupling and a C(sp³)–C(sp²) bond formation via reductive coupling.

Merging Organocatalysis with 1,2-Boronate Rearrangement: A Lewis Base-Catalyzed Asymmetric Multicomponent Reaction

H.-C. Shen & V. K. Aggarwal*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11113) 🔓

Catalytic asymmetric multicomponent 1,2-boronate rearrangements provide a practical approach for synthesizing highly valuable enantioenriched boronic esters. When applied to alkenyl or heteroaryl boronates, these reactions have relied mainly on transition-metal catalysis. Herein, the authors present an organocatalytic, Lewis base-catalyzed asymmetric multicomponent 1,2-boronate rearrangement, involving indoles, boronic esters, and Morita–Baylis–Hillman carbonates, leading to enantioenriched, highly substituted indole and indoline derivatives. Using cinchona alkaloid-based catalysts, high selectivity has been achieved, enabling expansion of the chemical space around pharmaceutically relevant indole and indoline derivatives.

Copper-Catalyzed Enantioselective [4π+2σ] Cycloaddition of Bicyclobutanes with Nitrones

X.-G. Zhang, Z.-Y. Zhou, J.-X. Li, J.-J. Chen & Q.-L. Zhou*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10123)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-4jd9l) 🔓

The selective construction of bridged bicyclic scaffolds has garnered increased attention due to their extensive use as saturated bioisosteres of arenes in the pharmaceutical industry. However, in contrast to their racemic counterparts, assembling chiral bridged bicyclic structures in an enantioselective and regioselective manner remains challenging. Herein, the authors describe their protocol for constructing chiral 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by enantioselective [4π+2σ] cycloadditions of bicyclo[1.1.0]butanes (BCBs) and nitrones taking advantage of a chiral copper(II) complex as a Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up to 99%), and excellent enantioselectivity (up to 99% e.e.).

Biocatalytic Synthesis of α-Amino Esters via Nitrene C–H Insertion

E. Alfonzo, D. Hanley, Z.-Q. Li, K. M. Sicinski, S. Gao & F. H. Arnold*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09989)

α-Amino esters are precursors to non-canonical amino acids used in developing small-molecule therapeutics, biologics, and tools in chemical biology. α-C–H amination of abundant and inexpensive carboxylic acid esters through nitrene transfer presents a direct approach to α-amino esters. Methods for nitrene-mediated amination of the protic α-C–H bonds in carboxylic acid esters, however, are underdeveloped. This study describes the discovery and evolution of highly stable protoglobin nitrene transferases that catalyze the enantioselective intermolecular amination of the α-C–H bonds in carboxylic acid esters. The authors developed a high-throughput assay to evaluate the activity and enantioselectivity of mutant enzymes together with their sequences using the Every Variant Sequencing (evSeq) method. The assay enabled the identification of enantiodivergent enzymes that function at ambient conditions in Escherichia coli whole cells and whose activities can be enhanced by directed evolution for the amination of a range of substrates.

ACS CATALYSIS

Reductive Olefin Bicyclo[1.1.0]butane Coupling Enabled by Iron Hydride Hydrogen Atom Transfer

G. Chen, D. Tian, X. Wang & H.-J. Zhang*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c04837)

The authors present a reductive olefin bicyclo[1.1.0]butane coupling method enabled by iron hydride hydrogen atom transfer. Readily available olefins can serve as competent C(sp³)-centered radical precursors, reacting with bicyclo[1.1.0]butanes to deliver valuable alkylated cyclobutanes. More than 40 examples are presented with a wide range of substrates, demonstrating the mildness of this operationally simple protocol.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION

Cross-Coupling of Gaseous Alkanes with (Hetero)Aryl Bromides via Dual Nickel/Photoredox Catalysis

A. M. Nair, P. Martínez-Balart, S. Barbeira-Arán & M. Fañanás-Mastral*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202416957)

Gaseous alkanes represent the most abundant carbon-based chemical feedstocks in our planet. However, the intrinsic inertness of their C-H bonds has rendered the use of these alkanes very difficult for purposes beyond aerobic combustion and energy intensive processes. Thus, clean and energy-efficient transformations for their use in synthetic organic chemistry are still rare. Here, the authors report a catalytic methodology for the direct cross-coupling of gaseous alkanes with (hetero)aryl bromides through the combination of metallaphotoredox-mediated hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for the addition of short alkyl groups into diverse (hetero)aromatic rings, providing a wide range of high-value alkyl(hetero)arenes, and bypassing the longstanding need of using preactivated alkylating agents in C(sp²)-C(sp³) cross-couplings. The method features high chemoselectivity, regioselectivity and a remarkable functional group tolerance, operates under mild conditions, and exhibits operational simplicity

CHEMRXIV

Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions

Á. D. Hernández-Mejías, A. M. Shimozono, A. Hazra, S. Richter, Z. Tong, N. F. Langille, K. Quasdorf, A. T. Parsons, M. S. Sigman* & S. E. Reisman*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-3r6z4) 🔓

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, the authors describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched β-alkyl acids.

Anomeric Nitroamide Enabled, Cobalt Catalyzed Alkene Hydronitration

Y. Wang, M. M. Bogner, J. B. Bailey, L. N. Grant, M. Gembicky, P. F. Richardson & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-s1mhh) 🔓

Tertiary nitroalkanes, as well as their reduced products, α-tertiary amines, play an essential role in drug discovery either as key synthetic precursors or for final incorporation into target molecules. Existing methods to prepare tertiary nitro compounds generally rely on polar-bond disconnections, in which strong bases or highly active electrophiles are needed. Here, the authors report the development of an anomeric nitroamide-based reagent that enables exquisitely selective MHAT-based Co-catalyzed alkene hydronitration for the preparation of valuable tertiary nitro compounds. This mild, scalable reaction shows broad functional group tolerance and has been applied to a variety of structures including the late-stage nitration of complex examples derived from drugs and natural products. The anomeric nitroamide reagent was deemed safe by energetic measurements and its unique reactivity rationalized based on X-ray crystallographic analysis.

Synthesis of Chiral δ-Aminoboronic Esters by Enantioselective Hydrogenation of 1,2-Azaborines

J. Liu, D. Robinson, B. Li and S.-Y. Liu*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-tk90h) 🔓

The authors report an enantio- and diastereoselective iridium-catalyzed hydrogenation of 1,2-azaborines to access δ-aminoboronic esters of potential biological importance. This method represents the first enantioselective hydrogenation of a boron-containing heteroarene and features a diverse substitution pattern and wide scope. The synthetic utility of the method was demonstrated by the synthesis of (–)-Phenibut and the formal synthesis of (+)-3-PPP and Fluvirucinine A1.

Simple, Enantiocontrolled Azetidine Library Synthesis via Strain Release Functionalization of 1-Azabicyclobutanes

M. Bielecki,^† M. Nassir,^† H. A. Sharma,^† N. J. Truax, N. Raheja, T. M. Thompson, T. E.-H. Ewing, B. Melillo, B. F. Cravatt* & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-cmvd4) 🔓

A simple, modular, programmable approach to access complex stereopure azetidines through strain-release functionalization is disclosed. The synthetic methods developed enable parallel synthesis of stereodefined azetidines that would be otherwise laborious to produce. Given the privileged nature of these structures, a set of stereoprobes for use in activity-based protein profiling was prepared and evaluated, revealing proteins in human cancer cells with were liganded with clear stereo- and chemo-selectivity.

Total Synthesis of Three Classes of Ring C-seco Limonoids

S. Jin & D. Ma*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-dscn9) 🔓

The nimbin-type, salannin-type and nimbolinin-type are three structurally related classes of ring C-seco limonoids possessing a complicated hexacyclic framework with a broad range of biological activities. Herein, a convergent and divergent route to access these classes was disclosed by the efficient and protecting-group-free syntheses of 52 ring C-seco limonoids. Key transformations include: 1) a catalytic asymmetric intermolecular Diels-Alder reaction to forge the A-ring bearing desired stereochemistry at C4 and C5; 2) a diastereoselective Pd-catalyzed reductive Heck reaction for the formation of the C8-C9 bond; 3) a sulfonyl hydrazone-mediated etherification and a regioselective 5-exo-trig radical cyclization for construction of the central tetrahydrofuran ring of the natural products; 4) BF₃·Et₂O-promoted biomimetic skeletal rearrangement reaction of the salannin-type to generate the nimbolinin-type.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE:

• In 1931, Linus Pauling (notably, the only person to have won two undivided Nobel Prizes and one of only two people to have won them in different fields—the other being Marie Curie) proposed the concept of a covalent one-electron σ-bond. In more recent years, heteroatom one-electron bonds have been observed but only now, nearly a century after Pauling’s proposal, have a team from Japan isolated and characterised a compound containing a carbon–carbon one-electron σ-bond. Summary of the research here.

• A new study published in Cell reports the results of a one-year single patient, phase I clinical trial, in which a woman with type 1 diabetes received a transplant of her own reprogrammed stem cells and in only 75-days post-operation, achieved sustained insulin independence, a feat that has now continued for over a year. Summary of the research here.